Nuclear receptor LRH-1/NR5A2 is required and targetable for liver endoplasmic reticulum stress resolution

• Main Authors: Jennifer L Mamrosh, Jae Man Lee, Martin Wagner, Peter J Stambrook, Richard J Whitby, Richard N Sifers, San-Pin Wu, Ming-Jer Tsai, Francesco J DeMayo, David D Moore
• Format: Article
• Language: English
• Published: eLife Sciences Publications Ltd 2014-04-01
• Series: eLife
• Subjects: ER stress; nuclear receptor; liver metabolism
• Online Access: https://elifesciences.org/articles/01694

Chronic endoplasmic reticulum (ER) stress results in toxicity that contributes to multiple human disorders. We report a stress resolution pathway initiated by the nuclear receptor LRH-1 that is independent of known unfolded protein response (UPR) pathways. Like mice lacking primary UPR components, hepatic Lrh-1-null mice cannot resolve ER stress, despite a functional UPR. In response to ER stress, LRH-1 induces expression of the kinase Plk3, which phosphorylates and activates the transcription factor ATF2. Plk3-null mice also cannot resolve ER stress, and restoring Plk3 expression in Lrh-1-null cells rescues ER stress resolution. Reduced or heightened ATF2 activity also sensitizes or desensitizes cells to ER stress, respectively. LRH-1 agonist treatment increases ER stress resistance and decreases cell death. We conclude that LRH-1 initiates a novel pathway of ER stress resolution that is independent of the UPR, yet equivalently required. Targeting LRH-1 may be beneficial in human disorders associated with chronic ER stress.